ClinVar

Description

This variant is denoted CDH1 c.2343A>T at the cDNA level, p.Glu781Asp (E781D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). This variant has been suggested in several in vitro assays to result in instability of E-cadherin at the plasma membrane with a possible effect on cell-cell adhesion (Figueiredo 2013, Sanches 2014). However, results of in vitro invasion assays are not consistent (Kaurah 2007, Figueiredo 2013) and an in vitro motility assay concluded that CDH1 Glu781Asp functioned similar to a wild-type control (Mateus 2009). While this variant has been reported in one unaffected individual with a family history of gastric cancer and one individual with a personal history of gastric cancer, segregation analysis was not completed in either family (Kaurah 2007, Benusiglio 2013). Importantly, the reported phenotypes of internal observations at this laboratory are not suggestive of Hereditary Diffuse Gastric Cancer (HDGC). In addition, in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. CDH1 Glu781Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. CDH1 Glu781Asp occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located within the cytoplasmic domain and p120-catenin and Hakai binding regions (Figueiredo 2013). Based on internal and published data, we consider CDH1 Glu781Asp to be a variant of uncertain significance.Published cancer risks have been primarily gathered from families with truncating pathogenic variants; therefore, the clinical significance of CDH1 missense variants in general, including those that show a functional impact in in vitro assays, is still undefined. Thus, we cannot rule out the possibility that this variant confers some elevated cancer risk; however, based on internal observations of families without gastric cancer, we are not able to assess whether this variant causes HDGC.